MOLECULAR BIOMARKERS OF EXPOSURE AND SUSCEPTIBILITY IN HUMAN COLON CANCER

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A major route of exposure to environmental carcinogens is through the diet. Epidemiological studies indicate the 20 to 50 percent of all human cancers can be attributed to dietary causes. The frequent consumption of animal fat, red meats, or grilled/smoked meats has been associated with increased risk for cancers of the gastrointestinal tract and pancreas. In contrast to the strong association between aflatoxin and liver cancer described in other projects in this program, the specific etiologic agents responsible for causing many diet- associated human cancers have yet to be determined. Two classes of chemical carcinogens, polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (Has), have been indentified in grilled or fried meats. These chemicals produce a variety of cancers, including colon, stomach, breast, and liver cancers, in experimental animal models. The overall goals of this project are to investigate the role of these dietary carcinogens in colon carcinogenesis in humans, and to identify susceptibility factors (effect modifiers) that modulate the metabolism of these carcinogens and, ultimately, colon polyp/cancer risk. Our work hypothesis is that ingestion of dietary carcinogens formed in meat during cooking is a causative factor in the formation of colon polys, preneoplastic lesions that occur early in the process of human colon cancer development. This project (Aim 1 and 2) will examine inter- individual differences in urinary HA and PAH metabolite profiles in subjects ingesting fried or broiled meat during controlled feeding studies. Relevant metabolic phenotypes and potential confounders will be assessed to investigate their role in intra-and inter-individual differences. These studies should provide insight into the biological basis for inter-individual variation in response to ingestion of carcinogens found in cooked meats. This project ( Aim 3 and 4) will also evaluate the association of these biomarkers of exposure and metabolism with risk of colon polyp development in a case-control and a case-case study. The identification of critical metabolic and dietary determinants of colon polyp risk should lead to new approaches for prevention of colon polyps and cancer.